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1.
Cancer Cell ; 42(2): 283-300.e8, 2024 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-38181797

RESUMO

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations. NK cells show reduced cytotoxicity and T cells have a dysfunctional profile. Interaction analysis reveals a vast immunoregulatory network and identifies NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduces neuroblastoma growth, with complete responses (CR) in vivo. Moreover, addition of TIGIT+PD-L1 blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.


Assuntos
Antígeno B7-H1 , Neuroblastoma , Humanos , Criança , Recidiva Local de Neoplasia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Receptores Imunológicos/genética , Imunoterapia , Análise de Sequência de RNA
2.
Eur J Cancer ; 194: 113347, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37832507

RESUMO

Immunotherapy has ignited hope to cure paediatric solid tumours that resist traditional therapies. Among the most promising methods is adoptive cell therapy (ACT). Particularly, ACT using T cells equipped with chimeric antigen receptors (CARs) has moved into the spotlight in clinical studies. However, the efficacy of ACT is challenged by ACT-intrinsic factors, like lack of activation or T cell exhaustion, as well as immune evasion strategies of paediatric solid tumours, such as their highly immunosuppressive microenvironment. Novel strategies, including ACT using innate-like lymphocytes, innovative cell engineering techniques, and ACT combination therapies, are being developed and will be crucial to overcome these challenges. Here, we discuss the main classes of ACT for the treatment of paediatric extracranial solid tumours, reflect on the available preclinical and clinical evidence supporting promising strategies, and address the challenges that ACT is still facing. Ultimately, we highlight state-of-the-art developments and opportunities for new therapeutic options, which hold great potential for improving outcomes in this challenging patient population.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Criança , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Linfócitos T , Imunoterapia , Microambiente Tumoral
3.
J Vis Exp ; (168)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33645564

RESUMO

Invariant Natural Killer T (iNKT) cells are innate-like T Lymphocytes expressing a conserved semi-invariant T cell receptor (TCR) specific for self or microbial lipid antigens presented by the non-polymorphic MHC class I-related molecule CD1d. Preclinical and clinical studies support a role for iNKT cells in cancer, autoimmunity and infectious diseases. iNKT cells are very conserved throughout species and their investigation has been facilitated by mouse models, including CD1d-deficient or iNKT-deficient mice, and the possibility to unequivocally detect them in mice and men with CD1d tetramers or mAbs specific for the semi-invariant TCR. However, iNKT cells are rare and they need to be expanded to reach manageable numbers for any study. Because the generation of primary mouse iNKT cell line in vitro has proven difficult, we have set up a robust protocol to purify and expand splenic iNKT cells from the iVα14-Jα18 transgenic mice (iVα14Tg), in which iNKT cells are 30 times more frequent. We show here that primary splenic iVα14Tg iNKT cells can be enriched through an immunomagnetic separation process, yielding about 95-98% pure iNKT cells. The purified iNKT cells are stimulated by anti-CD3/CD28 beads plus IL-2 and IL-7, resulting in 30-fold expansion by day +14 of the culture with 85-99% purity. The expanded iNKT cells can be easily genetically manipulated, providing an invaluable tool to dissect mechanisms of activation and function in vitro and, more importantly, also upon adoptive transfer in vivo.


Assuntos
Separação Celular/métodos , Células T Matadoras Naturais/imunologia , Animais , Antígenos CD4/metabolismo , Proliferação de Células , Ativação Linfocitária/imunologia , Camundongos , Células T Matadoras Naturais/citologia , Baço/citologia
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